Inexact Copies: How Generics
Differ From Brand Names

By

Melinda Beck

Updated April 22, 2008 12:01 a.m. ET

Joe Zealberg, a psychiatrist in Charleston, S.C., prescribed generic drugs to patients for years and rarely had problems -- until last year. A number of patients who had done very well on brand-name medications "crashed and burned" when they switched to generics, he says.

One woman "went from being perfectly fine to crying inconsolably 24 hours a day" after she switched from one generic antidepressant to another, Dr. Zealberg says. Another patient was sold a generic version of his attention-deficit drug that contained no identifying markings whatsoever -- a violation of federal rules.

Forum

Ten of his patients switched to a new generic version of the antidepressant Wellbutrin, but eight of them changed back, saying they felt anxious or shaky or their depression had returned. Several complained that the generic drug had a bad smell, he says.

Generic medications have been a boon to consumers around the world, allowing millions to buy lifesaving drugs for pennies a day. Some 65% of all prescriptions dispensed in the U.S. are for generics, though they account for only 20% of the dollars spent, according to the Generic Pharmaceutical Association.

While there is no hard evidence of growing problems from generics, consumers and physicians are increasingly concerned as cost pressures push more patients away from brand-name drugs. At the same time, the globalization of pharmaceutical manufacturing has revealed regulatory lapses.

By law, generics must have the same active ingredient and the same action as the brand-name version, which allows them to piggyback on the original safety and efficacy trials. But generics do have different inactive ingredients, which can affect how they are absorbed into the body. Generics can produce blood levels as much as 20% below or 25% above that of the original drug and still be considered "bioequivalent," according to Food and Drug Administration guidelines.

Some patients are more sensitive to those differences than others, and people who experience problems with medications are advised to contact their doctors, the drug manufacturer and the FDA's MedWatch. But as an FDA report last week on generic Wellbutrin revealed, consumers who complain may not get much satisfaction.

ENLARGE

Many patients switched from Wellbutrin XL 300 mg to Teva's Budeprion (right); a few have gone back.

Wellbutrin, made by Biovail Corp. of Canada and marketed by GlaxoSmithKline PLC, is one of the best-selling antidepressants in the U.S., with sales of $1.8 billion in 2006. The FDA approved a generic version of Wellbutrin XL 300, a long-acting once-daily version, in December 2006. The generic, named Budeprion XL 300, soon accounted for roughly 40% of the one million monthly prescriptions for the antidepressant.

But patients soon started logging complaints about Budeprion at PeoplesPharmacy.com, a Web site that has become a clearinghouse for medication gripes. "We've received hundreds of complaints about generic drugs in general. But with this one drug, all of a sudden -- kaboom -- right after it was approved," says Joe Graedon, a pharmacologist who runs People's Pharmacy with his wife. Readers' postings cite side effects such as tremors, headaches, anxiety and sleep disturbances. Some consumers said their depression had returned, in some cases bringing thoughts of suicide. Many reported that their adverse effects stopped when they returned to the brand-name drug.

Mr. Graedon alerted the FDA. He also asked ConsumerLab.com, which normally runs tests for dietary supplement manufacturers, to compare Budeprion and Wellbutrin. Using a test-tube test that some industry experts question, ConsumerLab found that Budeprion dissolves faster, releasing 34% of the drug within the first two hours, compared with 8% for Wellbutrin.

"If you get four times the drug in the first two hours, that's too much drug in the beginning and not enough for the rest of the day," says Mr. Graedon, who worries that what he calls "dose dumping" could cause seizures, a concern with the brand-name drug as well.

Complaints about Budeprion also were coming into the FDA -- at least 130 from December 2006 to January 2008, according to Andy Georgiades of Dow Jones News Service, who filed a Freedom of Information Act request. Only four complaints were filed about two rival generic versions of Wellbutrin XL 300 that went on the market in June 2007.

FDA Investigates

The FDA conducted an investigation and reported last week that although there were "small differences" between the two formulations, "they are not outside the established boundaries for equivalence." The generic did reach its maximum blood concentration in two to three hours, compared to five to six hours for Wellbutrin, but the FDA said those differences "were not considered clinically significant."

What accounted for the consumer complaints? The FDA cited "the natural history of depression," in which some patients have a recurrence of symptoms even while on medication.

Alarm Bells

How to Report Drug Problems

If you have a bad reaction to a drug or concerns about quality, your first stop should be your doctor, who can file a medical report with the FDA.

You can also submit a consumer report to the FDA's MedWatch program at www.fda.gov/MedWatch. You will be asked to describe the medication, the adverse event and some brief medical history. Your identity isn't requested. If you supply an email address, you will receive confirmation that your report was received. You can also speak to an FDA representative at 1-888-INFO-FDA .

Contact the manufacturer or distributor. The FDA requires prescription and over-the-counter drugs to list contact information on the packaging.

Return the medication to the pharmacist; use one you know and trust.

www.PeoplesPharmacy.com also logs complaints about generic drugs, but these aren't counted as official FDA adverse-event reports.

Some critics say the FDA, in effect, was saying, "it's all in their heads." But they were more alarmed to read in the report that the FDA relied on tests comparing a lower dose of Wellbutrin and Budeprion -- 150 mg -- when it first approved the 300 mg version in 2006, and didn't have specific bioequivalence data on the 300 mg dose that had generated the complaints.

"Everybody involved in this whole chain -- pharmacists, physicians, insurance companies, drug-store buyers -- assumes the FDA approves every single generic formulation to prove that it isn't harmful," says Mr. Graedon. "We learned last week that that's not the case."

The FDA explained that it didn't want to expose test subjects to the risk of seizures with the 300 mg dose. Bioequivalence tests are conducted on healthy people, not those who need the medication, and each gets just a single dose, so there is no chance to work up to 300 mg slowly, as actual patients are advised to do. Sandy Walsh, an FDA spokeswoman, says this is common procedure for testing antidepressants and antipsychotics.

"If we see scientific evidence that a product is not performing as expected, we will take action," Ms. Walsh says. "The FDA cannot offer examples where generics have not performed as expected because there have been none for the agency to report."

Bioequivalent

Deborah Jaskot, vice president for regulatory affairs at Teva Pharmaceuticals USA, which distributes Budeprion, says the ConsumerLab dissolution test was an invalid comparison, and that on all the accepted tests, Budeprion performed within the range of bioequivalence with Wellbutrin. Teva itself has received 101 reports of problems with Budeprion -- out of 4.5 million prescriptions written -- and hasn't heard reports of unusual smells, a spokeswoman says.

Ms. Jaskot also says Web sites that collect complaints about drugs "are doing the public a disservice." If consumers have problems with their medications they should "tell their physician, tell the manufacturer, tell the pharmacists, tell the FDA -- that's the only way these can get acted on and evaluated for veracity," she says.

But what if you complain to the FDA and are told, in effect, that your concerns are insignificant? As with so many other areas in health care, consumers have to be their own regulator and their own chief advocate.

"Consumers need to know that there are variations between generic drugs and brand-name drugs, and from one generic drug to another," says Wayne Pines, a former FDA spokesman who now consults for drug companies. "This is an area in which the patient has to be really self-protective, to be sure that they are getting the therapeutic effect that is best for them."

If you are taking a medication for a long-term condition, Mr. Pines advises staying with the version you are stabilized on. Some pharmacies sell generic versions interchangeably; tell your pharmacist you want to stay with the same one.

Monitor Symptoms

If you need to switch to a generic from a brand name for cost reasons, monitor your symptoms and review them with your doctor. Assess whether it's worth it to you to pay more. (There are some medications, particularly for thyroid and blood conditions, in which substitutions are never advised.)

The Graedons also recommend asking for copies of your lab reports, so you can help your doctor monitor any changes in your condition.

Be alert to changes in smell or appearance of your medications. Tell your doctor, pharmacist and the manufacturer if you notice anything odd.

Dr. Zealberg, however, is still waiting to hear back from the pharmacy that sold his patient blank pills.

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